Summary: Dr. Byrnes's work focuses on nonreplicating adenovirus vectors and how they behave in vivo. The cellular receptors used by the human adenoviruses that are currently in clinical trials are fairly well understood, yet the distribution of adenoviral receptors in various tissues does not directly predict how well these sites will be transduced by adenovirus vectors. After intravenous injection of adenoviral vectors, the majority of the vector is quickly phagocytosed by macrophages in the liver. This prevents the vector from reaching other organs, and leads to substantial cytokine release and hepatotoxicity. We have studied the distribution of adenovirus vectors in two rat models of liver cirrhosis. Surprisingly, after intravenous injection into cirrhotic rats, adenovirus vectors are quickly taken up by intravascular macrophages in the lungs, with greatly reduced uptake by macrophages in the liver. This phenomenon of pulmonary uptake has previously been reported in numerous human cases using the radiocolloid tracer 99m-Tc sulfur colloid, particularly in cases of congenital or acquired liver disease. This suggests that a subset of patients are at risk for unexpected pulmonary uptake of adenovirus vectors after intravenous or intraarterial administration. We are exploring whether pulmonary macrophage uptake of adenovirus vectors is associated with increased pathology.